Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are hormones released by the pituitary gland. These hormones regulate the functioning of the gonads and the production and maturation of gametes. LH and FSH are generally released by the pituitary gland upon prior release of a triggering hormone from the hypothalamus. Luteinizing hormone-releasing hormone (LHRH; also known as gonadotropin-releasing hormone or GnRH) is one of the principal hypothalamic hormones that triggers the release of LH and FSH. Thus, release of GnRH represents a control point in the physiological regulation of gonadal function.
LH and FSH release is necessary for ovulation in females and for maturation of sperm in males. Accordingly, compounds which inhibit LH and/or FSH release by blocking the action of GnRH, such as GnRH superagonists and antagonists, are useful in the treatment of sex-hormone associated disorders.
To decrease LH production, superagonists of the gonadotropin releasing hormone receptor (GnRH-R), such as leuprolide and goserelin, have been used. However, such GnRH superagonists initially act to stimulate LH release (and, frequently, testosterone or estrogen production) and only after prolonged treatment act to desensitize GnRH-R such that LH is no longer produced. In prostate cancer patients, for example, the initial stimulation of LH production by the superagonist leads to an initial surge in the production of male hormones such that the initial response to superagonist therapy is aggravation, rather than amelioration, of the patient's condition (e.g., tumor growth increases). This phenomenon, known as the “flare reaction”, can last for two to four weeks. Additionally, each successive administration of the superagonist can cause a small LH surge (known as the “acute-on chronic” phenomenon) that again can worsen the condition.
Antagonists of the gonadotropin releasing hormone receptor (GnRH-R) have been developed to overcome the flare reaction associated with GnRH agonists. A typical problem, however, that is frequently encountered with GnRH antagonist peptides is the occurrence of histamine-releasing activity. This histamine-releasing activity represents a serious obstacle to the clinical use of such antagonists because histamine release results in adverse side effects such as edema and itching. Many GnRH antagonist peptides also suffer from poor water-solubility, which complicates formulation of the antagonist for administration in vivo. Due to these characteristics, only a subset of GnRH antagonists are suitable for in vivo use.
Even among GnRH antagonists that have been used in vivo, such as Cetrorelix and Nal-Glu, it has been reported that while these antagonists reduced LH levels, they did not significantly affect FSH levels when the antagonist was administered to the subject in a single bolus injection (Reissmann T, et al. Human Reproduction (1995) 10(8):1974-81 and Diedrich K, et al. Human Reproduction (1994) 9(5):788-91).
Accordingly, GnRH antagonists that are suitable for use in vivo (e.g., they have high water solubility and low histamine-releasing activity) and that are able to inhibit LH and/or FSH production in a subject, are suitable for use in FSH related conditions, although prior attempts to reduce FSH levels with GnRH antagonists were inadequate.